Leptin Induces a Novel Form of NMDA Receptor-Dependent LTP at Hippocampal Temporoammonic-CA1 Synapses

Xiao Luo,Andrew J Irving,Jenni Harvey,Gemma Mcgregor

doi:10.1523/eneuro.0007-15.2015

Xiao Luo, Andrew J Irving + Show 2 more

Open Access

https://doi.org/10.1523/eneuro.0007-15.2015

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Abstract

It is well documented that the hormone leptin regulates many central functions and that hippocampal CA1 pyramidal neurons are a key target for leptin action. Indeed, leptin modulates excitatory synaptic transmission and synaptic plasticity at the Schaffer-collateral input to CA1 neurons. However the impact of leptin on the direct temporoammonic (TA) input to CA1 neurons is not known. Here we show that leptin evokes a long-lasting increase [long-term potentiation (LTP)] in excitatory synaptic transmission at TA-CA1 synapses in rat juvenile hippocampus. Leptin-induced LTP was NMDA receptor-dependent and specifically involved the activation of GluN2B subunits. The signaling pathways underlying leptin-induced LTP involve the activation of phosphoinositide 3-kinase, but were independent of the ERK signaling cascade. Moreover, insertion of GluA2-lacking AMPA receptors was required for leptin-induced LTP as prior application of philanthotoxin prevented the effects of leptin. In addition, synaptic-induced LTP occluded the persistent increase in synaptic efficacy induced by leptin. In conclusion, these data indicate that leptin induces a novel form of NMDA receptor-dependent LTP at juvenile TA-CA1 synapses, which has important implications for the role of leptin in modulating hippocampal synaptic function in health and disease.

Highlights

In order to ensure that we could discriminate between TA and SC inputs to CA1 neurons, we initially compared the effects of DA (100 ␮M) on excitatory synaptic transmission at TA and SC inputs to CA1 pyramidal neurons
Numerous studies indicate that leptin targets many extrahypothalamic brain regions, including the hippocampus, where it is a potent regulator of excitatory synaptic function (Harvey, 2007; Irving and Harvey, 2013)
We provide the first compelling evidence that, in contrast to the actions of leptin at classical SC-CA1 synapses, acute exposure to leptin induces a novel form of long-term potentiation (LTP) at TA-CA1 synapses in juvenile (P14 –P21) hippocampal slices

Summary

Introduction

It is well established that hippocampal CA1 pyramidal neurons receive two anatomically distinct glutamatergic. Proximal regions of apical dendrites in stratum radiatum (SR) indirectly receive inputs from the CA3 region via the Schaffer-collateral (SC) pathway. It has been shown that TA-CA1 synapses are strongly activated during cognitive tasks. There is evidence that activity-dependent synaptic plasticity induced at TA-CA1 synapses can modulate synaptic plasticity at SC-CA1 synapses (Levy et al, 1998; Remondes and Schuman, 2002, 2004). Recent evidence has shown that there are distinct differences in the functional expression of receptors between TA-CA1 and SC-CA1 synapses, and that synaptic activity induced by the two inputs is differentially regulated by neurotransmitters (Otmakhova and Lisman, 2000; Otmakhova et al, 2005)

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